Copper(I)-catalyzed three-component coupling leading to an efficient synthesis of β,γ-alkynyl α-amino acid derivatives

Article abstract of DOI:10.1055/s-2008-1067234

The first copper(I)-catalyzed direct three-component coupling of ethyl glyoxylate, p-anisidine, and terminal alkynes has been developed. This protocol provides an efficient method to prepare β,γ-alkynyl α-amino acid derivatives in good yields. Georg Thiem

Full text of DOI:10.1055/s-2008-1067234

2868
SHORT PAPER
Copper(I)-Catalyzed Three-Component Coupling Leading to an Efficient
Synthesis of b,g-Alkynyl a-Amino Acid Derivatives
b
, g-Alkynyl a-A
h
mino Acid D
i
erivat
h
a
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and Department of
Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, P. R. of China
Fax +852(904)23031590; E-mail: bcachan@polyu.edu.hk
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science
and Technology, Yunnan University, Kunming 650091, P. R. of China
b
Received 4 March 2008; revised 5 June 2008
ture-sensitive and inconvenient to handle. For practical
purposes, it is highly desirable to develop a more efficient
and direct method for the preparation of b,g-alkynyl a-
amino acid derivatives. More recently, Zhao’s group re-
ported a silver(I)-catalyzed three-component reaction for
the synthesis of a-aminopropargylphosphonates.6i Herein,
we describe the first copper(I)-catalyzed direct three-
component coupling of ethyl glyoxylate, p-anisidine, and
terminal alkynes. This reaction provides an efficient syn-
thetic approach to N-PMP-protected b,g-alkynyl a-amino
acid derivatives.
Abstract: The first copper(I)-catalyzed direct three-component
coupling of ethyl glyoxylate, p-anisidine, and terminal alkynes has
been developed. This protocol provides an efficient method to pre-
pare b,g-alkynyl a-amino acid derivatives in good yields.
Key words: copper, catalysis, multicomponent reactions, b,g-alky-
nyl a-amino acids
Transition-metal-catalyzed multicomponent reaction
(MCR) is a powerful synthetic tool for accessing complex
structures from simple precursors in a one-pot procedure.1
The discovery and development of MCRs is an important
research field for the advancement of combinatorial
chemistry.2
An investigation on the feasibility of catalytic three-com-
ponent synthesis of b,g-alkynyl a-amino acid derivatives
was initially conducted by using ethyl glyoxylate (1), p-
anisidine (2), and 4-phenylbut-1-yne (3a) as the model
substrates. Following our findings in the two-component
version,7 we employed silver(I) triflate as a catalyst for the
three-component coupling reaction, and found that the de-
sired reaction took place to give the product 4a in 61%
yield after 36 hours using 4 Å molecular sieves as the dry-
ing agent.
b,g-Alkynyl a-amino acids are an important class of non-
proteinogenic a-amino acids. It is recognized that a-ethy-
nyl substituents can profoundly change the biological
properties of certain natural amino acids, converting them
from enzyme substrates into irreversible inhibitors with
potential therapeutic utility.3 However, methods that pro-
vide reliable and convenient access to b,g-alkynyl a-ami-
no acid derivatives are still limited due to the chemical
lability of these substances. The early methods in target-
ing these compounds involved a two-component coupling
of haloglycinates with either alkynyltin reagents4 under
reflux conditions or alkynylmagesium reagents at
–78 °C.5
Encouraged by this result, we screened several transition-
metal catalysts for their utility in the transformation
(Table 1). As shown in Table 1, silver(I) nitrate and sil-
ver(I) acetate proved to be poor catalysts for this reaction
(entry 2). Zinc(II) triflate, zinc(II) chloride, scandium(III)
triflate, copper(I) bromide, and copper(I) chloride did not
catalyze the desired reaction (entries 3–5). In contrast,
copper(II) triflate did promote the desired reaction, albeit
in low efficiency (entry 6). When benzene complex of
copper(I) triflate was employed in the reaction, the prod-
uct 4a was obtained in 70% yield (entry 7). Further im-
provement in yield (75%) was realized using magnesium
sulfate as the drying agent (entry 8). The three-component
reaction can also occur with a similar chemical yield
(77%) in the absence of any additive (entry 9).
Metal-catalyzed addition of terminal alkynes to imines,
which are either preformed or generated from aldehydes
and amines, represents one of the most convenient meth-
ods for obtaining propargylamines.6 Recently, we extend-
ed this reaction to a-imino esters and developed a facile
synthesis of b,g-alkynyl a-amino acid derivatives through
silver(I)-catalyzed addition of terminal alkynes to a-imino
esters.7 Based on this method, we realized the first catalyt-
ic asymmetric synthesis of b,g-alkynyl a-amino acid de-
rivatives with 48–91% ee by employing chiral copper(I)
complexes.8 However, these strategies relied on the use of
a-imino esters, which needs to be prepared and isolated
beforehand. In addition, these substrates are highly mois-
To probe the general utility of this newly developed three-
component coupling reaction, a variety of different termi-
nal alkynes were examined and the results are summa-
rized in Table 2. To our delight, three-component reaction
of alkylacetylenes 1a–e (entries 1–5) and phenylacetylene
(1g) (entry 7) afforded the corresponding b,g-alkynyl a-
amino acid derivatives in good yields. Noticeably, the 1-
ethynylcyclohexene gave the desired highly functional-
ized product 4f in 80% (entry 6).
SYNTHESIS 2008, No. 18, pp 2868–2870
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x.
x
x
.
2
0
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Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1067234; Art ID: F08208SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
b,g-Alkynyl a-Amino Acid Derivatives
2869
Table 1 Catalysts Screened in the Three-Component Reactiona
On the basis of the above experimental results, together
with several related literature reports,6b–j a speculative ten-
tative mechanism was proposed involving the activation
of the C–H bond of terminal alkyne by copper(I) catalyst
(Scheme 1). The copper acetylide intermediate reacted
with the a-imino ester generated in situ from the ethyl gly-
oxylate and p-anisidine to give the corresponding b,g-
alkynyl a-amino acid derivative and regenerated the cop-
per(I) catalyst.
OMe
NHPMP
CO2Et
O
catalyst
+
+
H
CO2Et
CH2Cl2, r.t.
Ph
Ph
3a
NH2
1
2
4a
Entry
Metal catalyst
AgOTf
Yield (%)b
1
2
3
4
5
6
7
8
9
61c
<5c
0c
PMP
MeO
NH
2 O
AgNO3, AgOAc
Zn(OTf)2, ZnCl2
Sc(OTf)3
N
R
Cu
CO2Et
CO2Et
+
H+
H2O
0c
PMP
HN
Cu+
R
H
0c
CO2Et
CuBr, CuCl
R
Cu(OTf)2
44c
70c
75d
77e
Scheme 1 Speculative mechanism for copper(I)-catalyzed three-
component coupling
CuOTf·0.5C6H6
CuOTf·0.5C6H6
CuOTf·0.5C6H6
In summary, we have developed a new one-pot, three-
component coupling reaction for the synthesis of b,g-
alkynyl a-amino acid derivatives from ethyl glyoxylate,
p-anisidine, and terminal alkynes in good yields. The
asymmetric version of this reaction is presently under ac-
tive investigation.9
a All reactions were performed with ethyl glyoxylate (0.26 mmol),
p-anisidine (0.25 mmol), 4-phenylbut-1-yne (0.5 mmol), and catalyst
(10 mol%) in anhyd CH2Cl2 (1.5 mL) at r.t.
b Isolated yield.
c 4 Å MS used as additive.
d MgSO4 used as additive.
e Without any additive.
1H NMR and 13C NMR spectra were recorded in CDCl3 on a Bruker
Avance DPX 400 (400 and 100 MHz, respectively) NMR spectrom-
eter at r.t. Chemical shifts (d) are expressed in ppm, and J values are
given in Hz. High-resolution mass spectra (HRMS) were recorded
by using the electrospray ionization (ESI) method on a Fisons VG
platform or a MAT-95 spectrometer (Finnigan-MAT, San Jose,
CA). All reactions were conducted under N2. All chemicals were
used as received without further purification unless otherwise stat-
ed. CH2Cl2 was distilled from CaH2. Flash column chromatography
was performed on silica gel (230–400 mesh).
Table 2 Copper(I)-Catalyzed Three-Component Reactiona
OMe
CuOTf.0.5C6H6
(10 mol%)
NHPMP
CO2Et
O
R
+
+
CH2Cl2, r.t.
H
CO2Et
R
NH2
1
2
3
4
b,g-Alkynyl a-Amino Acid Derivatives 4a–g; Typical Procedure
CuOTf·0.5C6H6 (6.3 mg, 0.025 mmol) was added to a dried 5 mL
reaction flask. CH2Cl2 (1.0 mL) was added under N2, followed by a
solution of ethyl glyoxylate (27 mg, 0.26 mmol), p-anisidine (31
mg, 0.25 mmol), and the terminal alkyne (0.5 mmol) in CH2Cl2 (0.5
mL). The resulting mixture was stirred at r.t. until TLC monitoring
showed the completion of the reaction. The crude mixture was pu-
rified by flash chromatography over silica gel using n-hexane–
EtOAc as eluent to give the products as oils.
Entry
1
Alkyne
Product
Yield (%)b
4a
77
74
Ph
2
4b
Ph
3
4
5
4c
4d
4e
71
73
61
2-(4-Methoxyphenylamino)-6-phenylhex-3-ynoic Acid Ethyl
Ester (4a)7
TMS
1H NMR (400 MHz, CDCl3): d = 7.34–7.21 (m, 5 H), 6.86–6.83 (m,
2 H), 6.72–6.69 (m, 2 H), 4.74 (br s, 1 H), 4.31 (q, 2 H, J = 7.0 Hz),
4.22 (br s, 1 H), 3.81 (s, 3 H), 2.85 (t, 2 H, J = 7.4 Hz), 2.56–2.51
(m, 2 H), 1.35 (t, 3 H, J = 7.1 Hz).
6
7
4f
80
81
Ph
4g
13C NMR (100 MHz, CDCl3): d = 169.3, 153.2, 140.4, 139.6, 128.4,
128.3, 126.2, 115.9, 114.7, 84.4, 75.9, 62.1, 55.6, 50.1, 34.7, 20.9,
14.0.
a All reactions were performed with ethyl glyoxylate (0.26 mmol),
p-anisidine (0.25 mmol), terminal alkyne (0.5 mmol), and
CuOTf·0.5C6H6 (10 mol%) in anhyd CH2Cl2 (1.5 mL) at r.t.
b Isolated yield.
Synthesis 2008, No. 18, 2868–2870 © Thieme Stuttgart · New York

2870
Z. Shao, A. S. C. Chan
SHORT PAPER
2-(4-Methoxyphenylamino)-5-phenylpent-3-ynoic Acid Ethyl
Ester (4b)8a
Hz), 4.27–4.24 (q, 2 H, J = 7.5 Hz), 3.76 (s, 3 H), 2.80–2.77 (t, 2 H,
J = 7.3 Hz), 2.49–2.46 (dt, 2 H, J = 7.3, 2.0 Hz), 1.31–1.28 (t, 3 H,
J = 7.5 Hz).
13C NMR (100 MHz, CDCl3): d = 169.1, 153.4, 139.5, 132.0, 128.8,
128.3, 122.2, 116.1, 114.9, 84.4, 84.2, 62.5, 55.7, 50.7, 14.2.
1H NMR (400 MHz, CDCl3): d = 7.29–7.22 (m, 5 H), 6.82–6.80 (m,
2 H), 6.73–6.71 (m, 2 H), 4.81 (m, 1 H), 4.29 (q, 2 H, J = 7.4 Hz),
3.76 (s, 3 H), 3.62 (d, 1 H, J = 1.9 Hz), 1.32 (t, 3 H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): d = 169.2, 153.3, 139.5, 136.1, 128.4,
127.8, 126.6, 116.1, 114.5, 82.6, 77.6, 62.2, 55.6, 50.2, 25.0, 14.1.
Acknowledgment
2-(4-Methoxyphenylamino)oct-3-ynoic Acid Ethyl Ester (4c)
1H NMR (400 MHz, CDCl3): d = 6.81–6.74 (m, 2 H), 6.72–6.62 (m,
2 H), 4.71–4.69 (m, 1 H), 4.26 (q, 2 H, J = 7.0 Hz), 4.18–3.16 (m, 1
H), 3.70 (s, 3 H), 2.20–2.16 (m, 2 H), 1.47–1.26 (m, 7 H), 0.87 (t, 3
H, J = 7.2 Hz).
13C NMR (100 MHz, CDCl3): d = 169.5, 153.2, 139.7, 115.9, 114.7,
85.3, 75.1, 62.1, 55.6, 50.2, 30.4, 21.8, 18.3, 14.0, 13.5.
We thank the Hong Kong Research Grants Council (PolyU 5002/
05P), the University Grants Committee Areas of Excellence
Scheme in Hong Kong (AoE P/10-01), the Hong Kong Polytechnic
University Areas of Strategic Development Fund, and National Na-
tural Science Foundation of China (20702044) for financial support
(to Z.S.).
HRMS (ESI): m/z calcd for C17H24NO3 [M + 1]+: 290.1756; found:
290.1768.
References
(1) Zhu, J. P.; Bienayme, H. Multicomponent Reactions; Wiley:
Weinheim, 2005.
2-(4-Methoxyphenylamino)hept-3-ynoic Acid Ethyl Ester (4d)
1H NMR (400 MHz, CDCl3): d = 6.85–6.82 (m, 2 H), 6.74–6.71 (m,
2 H), 4.76 (br s, 1 H), 4.33 (q, 2 H, J = 7.2 Hz), 4.24 (br s, 1 H), 3.80
(s, 3 H), 2.23–2.19 (m, 2 H), 1.55 (q, 2 H, J = 7.2 Hz), 1.35 (t, 3 H,
J = 7.2 Hz), 0.98 (t, 3 H, J = 7.4 Hz).
13C NMR (100 MHz, CDCl3): d = 169.5, 153.2, 139.7, 115.9, 114.7,
85.2, 75.2, 62.1, 55.6, 50.1, 21.8, 20.6, 14.0, 13.3.
(2) (a) Weber, L.; Illegen, K.; Almstetter, M. Synlett 1999, 366.
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(4) Williams, R. M.; Aldous, D. J.; Aldous, S. C. J. Org. Chem.
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HRMS (ESI): m/z calcd for C16H22NO3 [M + 1]+: 276.1600; found:
276.1597.
(5) Castelhano, A. L.; Horne, S.; Taylor, G. J.; Billedeau, R.;
Krantz, A. Tetrahedron 1988, 44, 5451.
2-(4-Methoxyphenylamino)-5-trimethylsilylpent-3-ynoic Acid
Ethyl Ester (4e)7
(6) (a) For selected examples, see: For a review, see: Zani, L.;
Bolm, C. Chem. Commun. 2006, 4263. (b) Wei, C. M.; Li,
C. J. J. Am. Chem. Soc. 2002, 124, 5638. (c) Koradin, C.;
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1H NMR (400 MHz, CDCl3): d = 6.71–6.68 (m, 2 H), 6.60–6.58 (m,
2 H), 4.63 (br s, 1 H), 4.18 (q, 2 H, J = 7.0 Hz), 4.09 (br s, 1 H), 3.66
(s, 3 H), 1.37 (d, 2 H, J = 2.7 Hz), 1.22 (t, 3 H, J = 7.2 Hz), 0.03 (s,
9 H).
13C NMR (100 MHz, CDCl3): d = 169.7, 153.1, 139.7, 115.9, 114.7,
83.2, 73.9, 62.0, 55.7, 50.2, 14.1, 7.1, –2.2.
4-Cyclohex-1-enyl-2-(4-methoxyphenylamino)but-3-ynoic Acid
Ethyl Ester (4f)
1H NMR (400 MHz, CDCl3): d = 6.75 (d, J = 5.6 Hz, 2 H), 6.33 (d,
J = 5.6 Hz, 2 H), 6.05 (br s, 1 H), 4.78 (br s, 1 H), 4.22 (q, J = 7.1
Hz, 2 H), 4.17 (br s, 1 H), 3.72 (s, 3 H), 2.03–1.99 (m, 4 H), 1.56–
1.49 (m, 4 H), 1.25 (t, J = 7.1 Hz, 3 H).
(7) Ji, J. X.; Yeung, T. T. L. A.; Wu, J.; Yip, C. W.; Chan, A. S.
C. Adv. Synth. Catal. 2004, 346, 42.
13C NMR (100 MHz, CDCl3): d = 169.2, 153.2, 139.6, 136.1, 119.8,
115.9, 114.7, 86.2, 81.3, 62.1, 55.6, 50.5, 28.9, 25.6, 22.1, 21.3,
14.0.
HRMS (ESI): m/z calcd for C19H24NO3 [M + 1]+: 314.1753; found:
314.1756.
(8) (a) Ji, J. X.; Wu, J.; Chan, A. S. C. Proc. Natl. Acad. Sci.
U.S.A. 2005, 102, 11196. (b) Shao, Z. H.; Wang, J.; Ding,
K.; Chan, A. S. C. Adv. Synth. Catal. 2007, 349, 2375.
(9) The promising enantioselectivity has been achieved in the
catalytic asymmetric three-component coupling reaction of
ethyl glyoxylate, p-anisidine, and terminal alkynes with
chiral ligands: Shao, Z. H.; Fan, B. M.; Li, Y. M.; Kwong, F.
K. Chan, A. S. C., work in progress.
2-(4-Methoxyphenylamino)-4-phenylbut-3-ynoic Acid Ethyl
Ester (4g)7
1H NMR (400 MHz, CDCl3): d = 7.28–7.25 (m, 2 H), 7.20–7.16 (m,
3 H), 6.80–6.78 (m, 2 H), 6.67–6.65 (m, 2 H), 4.69 (t, 1 H, J = 2.3
Synthesis 2008, No. 18, 2868–2870 © Thieme Stuttgart · New York